Pre-eclampsia (PE) is associated with an increased risk for diabetes mellitus (DM) for both mother and child. Similarly, the risk for DM and metabolic syndrome (MS) is increased for the offspring of women with DM during pregnancy. This is especially problematic among American Indian and Hispanic women who are at much higher risk for T2DM and PE and surely contributes to the growing problem of T2DM in Hispanic and American Indian youth. The overarching hypothesis is that the effects of maternal DM and PE combine to compound the risk of DM/MS in offspring by changing gene expression via epigenetic mechanisms and altering circulating factors. This effectively programs the offspring for later DM/MS. To test this, selected offspring of pregnant women with DM and at high risk for PE will be studied from birth to age 4 years. The first aim examines the effect of maternal T2DM alone and complicated by PE on growth, body composition, and metabolic indices. Standard anthropometric measures are obtained along with assessment of body composition by dual energy X-ray absorptiometry and magnetic resonance imaging. Serum glucose, insulin and lipid concentrations are determined along with measures of metabolic rate. The second aim tests the hypothesis that an infant born to DM mother ( PE) is exposed to repertoire of cytokines/inflammatory factors before birth that leads to unfavorable metabolic indices and body composition. The third aim maps epigenetic modifications in order to identify relevant target genes. The HELP assay is employed to identify variation in cytosine methylation at specific genetic loci in placental and leukocyte DNA. Defining the mechanisms, risk factors, and surrogate markers of future DM can lead new ways to prevent DM in high risk populations. PUBLIC HEALTH RELEVANCE: Obesity is increasing at an alarming rate in children and threatening their future health, especially among American Indians and Hispanics. This project examines the maternal factors that predispose to obesity and diabetes and how they affect preschool-aged children. This information will be useful in designing specific interventions and assessing their efficacy.